okadaic acid
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Okadaic acid, C44H68O13, is a toxin produced by several species of
dinoflagellate The dinoflagellates (Greek δῖνος ''dinos'' "whirling" and Latin ''flagellum'' "whip, scourge") are a monophyletic group of single-celled eukaryotes constituting the phylum Dinoflagellata and are usually considered algae. Dinoflagellates are ...
s, and is known to accumulate in both marine
sponge Sponges, the members of the phylum Porifera (; meaning 'pore bearer'), are a basal animal clade as a sister of the diploblasts. They are multicellular organisms that have bodies full of pores and channels allowing water to circulate through t ...
s and
shellfish Shellfish is a colloquial and fisheries term for exoskeleton-bearing aquatic invertebrates used as food, including various species of molluscs, crustaceans, and echinoderms. Although most kinds of shellfish are harvested from saltwater envir ...
. One of the primary causes of
diarrhetic shellfish poisoning Diarrhetic shellfish poisoning (DSP) is one of the four recognized symptom types of shellfish poisoning, the others being paralytic shellfish poisoning, neurotoxic shellfish poisoning and amnesic shellfish poisoning. As the name suggests, this sy ...
, okadaic acid is a potent inhibitor of specific protein
phosphatase In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid Ester, monoester into a phosphate ion and an Alcohol (chemistry), alcohol. Because a phosphatase enzyme catalysis, catalyzes the hydrolysis of its Substrate ...
s and is known to have a variety of negative effects on cells. A
polyketide Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynth ...
,
polyether In organic chemistry, ethers are a class of compounds that contain an ether group—an oxygen atom connected to two alkyl or aryl groups. They have the general formula , where R and R′ represent the alkyl or aryl groups. Ethers can again be c ...
derivative of a C38
fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, fr ...
, okadaic acid and other members of its family have shined light upon many biological processes both with respect to dinoflagellete polyketide synthesis as well as the role of protein
phosphatase In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid Ester, monoester into a phosphate ion and an Alcohol (chemistry), alcohol. Because a phosphatase enzyme catalysis, catalyzes the hydrolysis of its Substrate ...
s in
cell growth Cell growth refers to an increase in the total mass of a cell, including both cytoplasmic, nuclear and organelle volume. Cell growth occurs when the overall rate of cellular biosynthesis (production of biomolecules or anabolism) is greater than ...
.


History

As early as 1961, reports of
gastrointestinal disorders Gastrointestinal diseases (abbrev. GI diseases or GI illnesses) refer to diseases involving the gastrointestinal tract, namely the oesophagus, stomach, small intestine, large intestine and rectum, and the accessory organs of digestion, the live ...
following the consumption of cooked mussels appeared in both the Netherlands and Los Lagos. Attempts were made to determine the source of the symptoms, however they failed to elucidate the true culprit, instead implicating a species of microplanctonic
dinoflagellate The dinoflagellates (Greek δῖνος ''dinos'' "whirling" and Latin ''flagellum'' "whip, scourge") are a monophyletic group of single-celled eukaryotes constituting the phylum Dinoflagellata and are usually considered algae. Dinoflagellates are ...
s. In the summers of the late 1970s, a series of
food poisoning Foodborne illness (also foodborne disease and food poisoning) is any illness resulting from the spoilage of contaminated food by pathogenic bacteria, viruses, or parasites that contaminate food, as well as prions (the agents of mad cow disease) ...
outbreaks in Japan lead to the discovery of a new type of shellfish poisoning. Named for the most prominent symptoms, the new
Diarrhetic Shellfish Poisoning Diarrhetic shellfish poisoning (DSP) is one of the four recognized symptom types of shellfish poisoning, the others being paralytic shellfish poisoning, neurotoxic shellfish poisoning and amnesic shellfish poisoning. As the name suggests, this sy ...
(DSP) only affected the northern portion of
Honshu , historically called , is the largest and most populous island of Japan. It is located south of Hokkaidō across the Tsugaru Strait, north of Shikoku across the Inland Sea, and northeast of Kyūshū across the Kanmon Straits. The island separ ...
during 1976, however by 1977 large cities such as
Tokyo Tokyo (; ja, 東京, , ), officially the Tokyo Metropolis ( ja, 東京都, label=none, ), is the capital and largest city of Japan. Formerly known as Edo, its metropolitan area () is the most populous in the world, with an estimated 37.468 ...
and
Yokohama is the second-largest city in Japan by population and the most populous municipality of Japan. It is the capital city and the most populous city in Kanagawa Prefecture, with a 2020 population of 3.8 million. It lies on Tokyo Bay, south of To ...
were affected. Research into the shellfish consumed in the affected regions showed that a fat-soluble toxin was responsible for the 164 documented cases, and this toxin was traced to mussels and scallops harvested in the
Miyagi prefecture is a prefecture of Japan located in the Tōhoku region of Honshu. Miyagi Prefecture has a population of 2,305,596 (1 June 2019) and has a geographic area of . Miyagi Prefecture borders Iwate Prefecture to the north, Akita Prefecture to the nort ...
. In northeastern Japan, a legend had existed that during the season of
paulownia ''Paulownia'' ( ) is a genus of seven to 17 species of hardwood tree (depending on taxonomic authority) in the family Paulowniaceae, the order Lamiales. They are present in much of China, south to northern Laos and Vietnam and are long cultivat ...
flowers, shellfish can be poisonous. Studies following this outbreak showed that toxicity of these mussels and scallops appeared and increased during the months of June and July, and all but disappeared between August and October. Elsewhere in Japan, in 1975 Fujisawa pharmaceutical company observed that the extract of a black sponge, ''Halichondria okadai'', was a potent
cytotoxin Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are an immune cell or some types of venom, e.g. from the puff adder (''Bitis arietans'') or brown recluse spider (''Loxosceles reclusa''). Cell physiology Treating c ...
, and was dubbed Halichondrine-A. In 1981, the structure of one such toxin, okadaic acid, was determined after it was extracted from both the black sponge in Japan, ''Halichondria okadai'', for which it was named, and a sponge in the
Florida Keys The Florida Keys are a coral cay archipelago located off the southern coast of Florida, forming the southernmost part of the continental United States. They begin at the southeastern coast of the Florida peninsula, about south of Miami, and e ...
, ''Halichondria melanodocia''. Okadaic acid sparked research both for its
cytotoxic Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are an immune cell or some types of venom, e.g. from the puff adder (''Bitis arietans'') or brown recluse spider (''Loxosceles reclusa''). Cell physiology Treating cells ...
feature and for being the first reported marine
ionophore In chemistry, an ionophore () is a chemical species that reversibly binds ions. Many ionophores are lipid-soluble entities that transport ions across the cell membrane. Ionophores catalyze ion transport across hydrophobic membranes, such as liq ...
. One of the toxic culprits of DSP, dinophysistoxin-1 (DTX-1), named for one of the organisms implicated in its production, ''
Dinophysis ''Dinophysis'' is a genus of dinoflagellatesAlgaeBase''Dinophysis'' Ehrenberg, 1839/ref> common in tropical, temperate, coastal and oceanic waters.Hallegraeff, G.M., Lucas, I.A.N. 1988: The marine dinoflagellate genus Dinophysis (Dinophyceae): ph ...
fortii'', was compared to and shown to be very chemically similar to okadaic acid several years later, and okadaic acid itself was implicated in DSP around the same time. Since its initial discovery, reports of DSP have spread throughout the world, and are especially concentrated in Japan, South America and Europe.


Synthesis


Derivatives

Okadaic acid (OA) and its derivatives, the dinophysistoxins (DTX), are members of a group of molecules called
polyketide Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynth ...
s. The complex structure of these molecules include multiple spiroketals, along with fused ether rings.


Biosynthesis

Being polyketides, the okadaic acid family of molecules are synthesized by
dinoflagellate The dinoflagellates (Greek δῖνος ''dinos'' "whirling" and Latin ''flagellum'' "whip, scourge") are a monophyletic group of single-celled eukaryotes constituting the phylum Dinoflagellata and are usually considered algae. Dinoflagellates are ...
s via
polyketide synthase Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynth ...
(PKS). However unlike the majority of polyketides, the dinoflagellate group of polyketides undergo a variety of unusual modifications. Okadaic acid and its derivatives are some of the most well studied of these polyketides, and research on these molecules via
isotopic labeling Isotopic labeling (or isotopic labelling) is a technique used to track the passage of an isotope (an atom with a detectable variation in neutron count) through a reaction, metabolic pathway, or cell. The reactant is 'labeled' by replacing specific ...
has helped to elucidate some of those modifications. Okadaic acid is formed from a starter unit of
glycolate Glycolic acid (or hydroxyacetic acid; chemical formula HOCH2CO2H) is a colorless, odorless and hygroscopic crystalline solid, highly soluble in water. It is used in various skin-care products. Glycolic acid is widespread in nature. A glycolate (so ...
, found at carbons 37 and 38, and all subsequent carbons in the chain are derived from
acetate An acetate is a salt (chemistry), salt formed by the combination of acetic acid with a base (e.g. Alkali metal, alkaline, Alkaline earth metal, earthy, Transition metal, metallic, nonmetallic or radical Radical (chemistry), base). "Acetate" als ...
. Because polyketide synthesis is similar to
fatty acid synthesis In biochemistry, fatty acid synthesis is the creation of fatty acids from acetyl-CoA and NADPH through the action of enzymes called fatty acid synthases. This process takes place in the cytoplasm of the cell. Most of the acetyl-CoA which is conve ...
, during chain extension the molecule may undergo reduction of the ketone, dehydration, and reduction of the olefin. Failure to perform one of more of these three steps, combined with several unusual reactions is what allows for the formation of the
functionality Function or functionality may refer to: Computing * Function key, a type of key on computer keyboards * Function model, a structured representation of processes in a system * Function object or functor or functionoid, a concept of object-oriente ...
of okadaic acid. Carbon deletion and addition at the alpha and beta position comprise the other transformations present in the okadaic acid biosynthesis. Carbon deletion occurs by way of a
Favorskii rearrangement The Favorskii rearrangement is principally a rearrangement of cyclopropanones and α-halo ketones that leads to carboxylic acid derivatives. In the case of cyclic α-halo ketones, the Favorskii rearrangement constitutes a ring contraction. This ...
and subsequent
decarboxylation Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2). Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is t ...
. Attack of a ketone in the growing chain by enzyme-bound acetates, and subsequent decarboxylation/dehydration results in an
olefin In organic chemistry, an alkene is a hydrocarbon containing a carbon–carbon double bond. Alkene is often used as synonym of olefin, that is, any hydrocarbon containing one or more double bonds.H. Stephen Stoker (2015): General, Organic, an ...
replacing the ketone, in both alpha and beta alkylation. After this the olefin can isomerize to more thermodynamically stable positions, or can be activated for cyclizations, in order to produce the natural product.


Laboratory Syntheses

To date, several studies have been performed toward the
synthesis Synthesis or synthesize may refer to: Science Chemistry and biochemistry *Chemical synthesis, the execution of chemical reactions to form a more complex molecule from chemical precursors ** Organic synthesis, the chemical synthesis of organ ...
of okadaic acid and its derivatives. 3
total syntheses Total synthesis is the complete chemical synthesis of a complex molecule, often a natural product, from simple, commercially-available precursors. It usually refers to a process not involving the aid of biological processes, which distinguishes ...
of okadaic acid have been achieved, along with many more formal syntheses and several total syntheses of the other dinophysistoxins. The first total synthesis of okadaic acid was completed in 1986 by Isobe et al., just 5 years after the molecule's structure was elucidated. The next two were completed in 1997 and 1998 by the Forsyth and Ley groups respectively. In Isobe's synthesis, the molecule was broken into 3 pieces, along the C14-C15 bonds, and the C27-C28 bonds. This formed fragments A, B, and C, which were all synthesized separately, after which the B and C fragments were combined, and then combined with the A fragment. This synthesis contained 106 steps, with a longest linear sequence of 54 steps. The precursors to all three fragments were all
glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...
derivatives obtained from the
chiral pool The chiral pool is a "collection of abundant enantiopure building blocks provided by nature" used in synthesis. In other words, a chiral pool would be a large quantity of common organic enantiomers. Contributors to the chiral pool are amino acids, ...
. Spiroketals were obtained from precursor ketone diols, and were therefore formed thermally in acid. Similar to Isobe's synthesis, the Forsyth synthesis sought to reduce the number of steps, and to increase potential for designing analogues late in the synthesis. To do this, Forsyth et al. designed the synthesis to allow for structural changes and installation of important functional groups before large pieces were joined. Their resulting synthesis was 3% yielding, with 26 steps in the longest linear sequence. As above, spiroketalization was performed thermodynamically with introduction of acid. Ley's synthesis of okadaic acid is most unlike its predecessors, although it still contains similar motifs. Like the others, this synthesis divided okadaic acid into three components along the acyclic segments. However, designed to display new techniques developed in their group, Ley's synthesis included forming the spiroketals using (diphenylphosphineoxide)-tetrahydrofuran and (phenylsulfonyl)-tetrahydropyrans, allowing for more mild conditions. Similar to those above, a portion of the
stereochemistry Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms that form the structure of molecules and their manipulation. The study of stereochemistry focuses on the relationships between stereois ...
in the molecule was set by starting materials obtained from the
chiral pool The chiral pool is a "collection of abundant enantiopure building blocks provided by nature" used in synthesis. In other words, a chiral pool would be a large quantity of common organic enantiomers. Contributors to the chiral pool are amino acids, ...
, in this case
mannose Mannose is a sugar monomer of the aldohexose series of carbohydrates. It is a C-2 epimer of glucose. Mannose is important in human metabolism, especially in the glycosylation of certain proteins. Several congenital disorders of glycosylation ...
.


Biology


Mechanism of Action

Okadaic acid (OA) and its relatives are known to strongly inhibit protein
phosphatase In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid Ester, monoester into a phosphate ion and an Alcohol (chemistry), alcohol. Because a phosphatase enzyme catalysis, catalyzes the hydrolysis of its Substrate ...
s, specifically serine/threonine phosphatases. Furthermore, of the 4 such phosphatases, okadaic acid and its relatives specifically target
protein phosphatase 1 Protein phosphatase 1 (PP1) belongs to a certain class of phosphatases known as protein serine/threonine phosphatases. This type of phosphatase includes metal-dependent protein phosphatases (PPMs) and aspartate-based phosphatases. PP1 has been fo ...
(PP1) and protein phosphatase 2A (PP2A), at the exclusion of the other two, with
dissociation constant In chemistry, biochemistry, and pharmacology, a dissociation constant (K_D) is a specific type of equilibrium constant that measures the propensity of a larger object to separate (dissociate) reversibly into smaller components, as when a complex fa ...
s for the two proteins of 150 nM and 30 pM respectively. Because of this, this class of molecules has been used to study the action of these phosphatases in cells. Once OA binds to the phosphatase protein(s), it results in
hyperphosphorylation Hyperphosphorylation occurs when a biochemical with multiple phosphorylation sites is fully saturated. Hyperphosphorylation is one of the signaling mechanisms used by the cell to regulate mitosis. When these mechanisms fail, developmental problems ...
of specific proteins within the afflicted cell, which in turn reduces control over sodium secretion and solute permeability of the cell. Affinity between okadaic acid and its derivatives and PP2A has been tested, and it was shown that the only derivative with a lower
dissociation constant In chemistry, biochemistry, and pharmacology, a dissociation constant (K_D) is a specific type of equilibrium constant that measures the propensity of a larger object to separate (dissociate) reversibly into smaller components, as when a complex fa ...
, and therefore higher
affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Par ...
, was DTX1, which has been shown to be 1.6 times stronger. Furthermore, for the purpose of determining the toxicity of mixtures of different okadaic acid derivatives, inhibitory equivalency factors for the relatives of okadaic acid have been studied. In wild type PP2A, the inhibitory equivalency relative to okadaic acid were 0.9 for DTX-1 and 0.6 for DTX-2.


Toxicology

The main route of exposure to
DSP DSP may refer to: Computing * Digital signal processing, the mathematical manipulation of an information signal * Digital signal processor, a microprocessor designed for digital signal processing * Yamaha DSP-1, a proprietary digital signal ...
from okadaic acid and its relatives is through the consumption of
shellfish Shellfish is a colloquial and fisheries term for exoskeleton-bearing aquatic invertebrates used as food, including various species of molluscs, crustaceans, and echinoderms. Although most kinds of shellfish are harvested from saltwater envir ...
. It was initially shown that the toxic agents responsible for DSP tend to be most concentrated in the
hepatopancreas The hepatopancreas, digestive gland or midgut gland is an organ of the digestive tract of arthropods and molluscs. It provides the functions which in mammals are provided separately by the liver and pancreas, including the production of digestive ...
, followed by the
gills A gill () is a respiratory organ that many aquatic organisms use to extract dissolved oxygen from water and to excrete carbon dioxide. The gills of some species, such as hermit crabs, have adapted to allow respiration on land provided they are ...
for certain shellfish. The symptoms for diarrhetic shellfish poisoning include intense diarrhea and severe abdominal pains, and rarely nausea and vomiting, and they tend to occur anytime between 30 minutes and at most 12 hours after consuming toxic shellfish. It has been estimated that it takes roughly 40 μg of okadaic acid to trigger diarrhea in adult humans.


Medical Uses

Because of its inhibitory effects in
phosphatases In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid monoester into a phosphate ion and an alcohol. Because a phosphatase enzyme catalyzes the hydrolysis of its substrate, it is a subcategory of hydrolases. ...
, okadaic acid has shown promise in the world of medicine for numerous potential uses. During its initial discovery, okadaic acid, specifically the crude source extract, showed potent inhibition of
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
cells, and so initial interest in the family of molecules tended to center around that feature. However, it was shown that the more cytotoxic component of ''H. Okadai'' was actually a separate family of compounds, the Halichondrines, and as such research into the
cytotoxicity Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are an immune cell or some types of venom, e.g. from the puff adder (''Bitis arietans'') or brown recluse spider (''Loxosceles reclusa''). Cell physiology Treating cells ...
of okadaic acid decreased. However, the unique function of okadaic acid upon cells maintained biological interest in the molecule. Okadaic acid has been shown to have neurotoxic, immunotoxic, and embryotoxic effects. Furthermore, in two-stage carcinogenesis of mouse skin, the molecule and its relatives have been shown to have tumor promoting effects. Because of this, the effects of okadaic acid on Alzheimer's, AIDS, diabetes, and other human diseases have been studied.


See also

*
Canadian Reference Materials Canadian Reference Materials (CRM) are certified reference materials of high-quality and reliability produced by the National Metrology Institute of Canada – the National Research Council (Canada), National Research Council Canada. The NRC Certifi ...
*
Brevetoxin Brevetoxin (PbTx), or brevetoxins, are a suite of cyclic polyether compounds produced naturally by a species of dinoflagellate known as '' Karenia brevis''. Brevetoxins are neurotoxins that bind to voltage-gated sodium channels in nerve cells, le ...
*
Ciguatoxin image:ciguatoxin.svg, 300px, Chemical structure of the ciguatoxin CTX1B Ciguatoxins are a class of toxic Polycyclic compound, polycyclic polyethers found in fish that cause ciguatera. There are several different chemicals in this class. "CTX" ...
*
Domoic acid Domoic acid (DA) is a kainic acid-type neurotoxin that causes amnesic shellfish poisoning (ASP). It is produced by algae and accumulates in shellfish, sardines, and anchovies. When sea lions, otters, cetaceans, humans, and other predators eat c ...
*
Saxitoxin Saxitoxin (STX) is a potent neurotoxin and the best-known paralytic shellfish toxin (PST). Ingestion of saxitoxin by humans, usually by consumption of shellfish contaminated by toxic algal blooms, is responsible for the illness known as paralytic ...
*
Tetrodotoxin Tetrodotoxin (TTX) is a potent neurotoxin. Its name derives from Tetraodontiformes, an order that includes pufferfish, porcupinefish, ocean sunfish, and triggerfish; several of these species carry the toxin. Although tetrodotoxin was discovered ...
* Rubratoxin


References


External links

* {{Use dmy dates, date=April 2020 Carboxylic acids Laxatives Phycotoxins Polyketides Polyether toxins Spiro compounds Oxygen heterocycles Phosphatase inhibitors